Affinage

TOP1

DNA topoisomerase 1 · UniProt P11387

Round 2 corrected
Length
765 aa
Mass
90.7 kDa
Annotated
2026-04-28
130 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TOP1 is a type IB DNA topoisomerase that relieves torsional stress generated during replication and transcription by clamping around duplex DNA, cleaving one strand via the active-site nucleophile Tyr-723 to form a covalent 3′-phosphotyrosyl intermediate (TOP1 cleavage complex, TOP1cc), allowing controlled rotation of the downstream duplex, and religating the nick (PMID:9488644, PMID:9488652). TOP1 acts cooperatively with TOP2 within ~600 bp of replication forks and at replication initiation; loss of both topoisomerases arrests fork progression and activates the DNA damage checkpoint (PMID:17671091, PMID:41791707). Camptothecin-class drugs trap the TOP1cc by intercalating at the cleavage site, and trapped complexes are resolved by redundant pathways including TDP1-mediated phosphotyrosyl hydrolysis, ERCC1-XPF/NER endonuclease cleavage, and MUS81-dependent processing after TOP1 proteolysis, with PARP1-dependent PARylation and SUMO/ubiquitin modifications further regulating TOP1cc dynamics and repair (PMID:12426403, PMID:12368472, PMID:26025908, PMID:37194054, PMID:27466387). Abortive TOP1 activity at genome-embedded ribonucleotides generates a characteristic 2–5 bp deletion mutational signature (ID4) contributing to both somatic and germline mutagenesis, and transcription-coupled TOP1cc formation at hypertranscribed loci cooperates with R-loops to produce DSBs and chromosomal translocations (PMID:35140396, PMID:37945566, PMID:38375218).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1985 High

    Establishing that TOP1 is dispensable for viability as a single mutant but essential in the absence of TOP2 defined the cooperative, partially redundant relationship between the two topoisomerases in chromosome metabolism.

    Evidence Yeast TOP1 deletion and top1Δ top2-ts double-mutant viability assays

    PMID:2997777

    Open questions at the time
    • Mechanistic basis of TOP1–TOP2 functional overlap at specific genomic loci was unknown
    • Whether TOP1 deletion affects replication fork dynamics was not addressed
  2. 1988 High

    Cloning of human TOP1 and mapping the catalytic activity to the C-terminal 67.7-kDa fragment containing Tyr-723 established the domain architecture and active-site residue of the human enzyme.

    Evidence cDNA cloning, in vitro DNA relaxation assay, proteolysis mapping

    PMID:2833744

    Open questions at the time
    • No three-dimensional structure available
    • Mechanism of strand rotation after cleavage was unknown
  3. 1998 High

    Crystal structures of human TOP1 covalently and noncovalently bound to DNA revealed the clamp architecture, confirmed Tyr-723 as the active-site nucleophile, and led to the controlled-rotation model for DNA relaxation.

    Evidence X-ray crystallography at 2.1–2.8 Å of TOP1–DNA complexes

    PMID:9488644 PMID:9488652

    Open questions at the time
    • Camptothecin binding site was inferred but not directly visualized
    • Open-to-closed conformational transition mechanism was not resolved
  4. 2002 High

    Identification of TDP1 and Rad1-Rad10 (ERCC1-XPF) as two redundant primary pathways for TOP1cc repair, both requiring downstream homologous recombination, established the framework for understanding TOP1cc-associated DNA damage responses.

    Evidence Yeast genetic epistasis with tdp1 rad1 double mutants, camptothecin sensitivity assays

    PMID:12368472

    Open questions at the time
    • Whether additional nucleases contribute to TOP1cc removal was unknown
    • The role of proteasomal degradation of TOP1 before nucleolytic processing was not defined
  5. 2002 High

    The ternary crystal structure of TOP1–DNA–Topotecan directly showed that the camptothecin pharmacophore intercalates at the cleavage site to block religation, establishing the structural basis for uncompetitive TOP1 inhibition.

    Evidence X-ray crystallography of TOP1–DNA–Topotecan ternary complex

    PMID:12426403

    Open questions at the time
    • Structural basis for newer inhibitors (e.g., exatecan) awaited direct crystallographic confirmation
    • How drug binding affects controlled rotation dynamics was not resolved
  6. 2007 High

    Genome-wide ChIP mapping showed TOP1 and TOP2 co-occupy a ~600 bp zone at replication forks; their combined loss but not single loss causes fork arrest and checkpoint activation, quantifying the redundancy at replication forks.

    Evidence ChIP genome-wide mapping of Top1/Top2 at replicating chromosomes in budding yeast, checkpoint kinase assays

    PMID:17671091

    Open questions at the time
    • Whether TOP1 contributes specifically to replication initiation was not addressed
    • Vertebrate confirmation of fork-proximal co-occupancy was lacking
  7. 2008 Medium

    Discovery that TOP1 catalytic activity promotes a repressed chromatin state at telomere-proximal regions and rDNA broadened TOP1 function beyond supercoil relaxation to include chromatin organization.

    Evidence Microarray expression profiling, ChIP, and catalytic-dead Y727F mutant analysis in yeast

    PMID:12215413 PMID:18272174

    Open questions at the time
    • Direct mechanism linking TOP1 catalysis to histone deacetylation was not identified
    • Whether this chromatin role is conserved in mammals was not tested
  8. 2015 High

    Biochemical reconstitution of ERCC1-XPF/RPA-mediated cleavage and repair synthesis on phosphotyrosyl-nick substrates established a complete NER-related repair pathway for TOP1cc in mammalian cells.

    Evidence In vitro nuclease assays on phosphotyrosyl-nick DNA, repair synthesis reconstitution, co-localization by immunofluorescence in CPT-treated cells

    PMID:26025908

    Open questions at the time
    • Relative contribution of NER versus TDP1 in different cell types was not quantified
    • Whether this pathway operates during transcription-associated TOP1cc was not addressed
  9. 2016 High

    Demonstration that TOP1 performs ribonucleotide-dependent deletions via a sequential double-cleavage mechanism at tandem repeats defined the enzymatic basis of TOP1-mediated mutagenesis.

    Evidence In vitro TOP1 cleavage assays on defined substrates paralleled by in vivo yeast mutation assays

    PMID:27257064

    Open questions at the time
    • Genome-wide prevalence of this mechanism in mammalian cells was not yet established
    • Whether deletion size is influenced by chromatin context was unknown
  10. 2016 High

    PARP1-mediated PARylation was shown to regulate TOP1 subnuclear dynamics, with PARP inhibition delocalizing TOP1 from the nucleolus and increasing genome-wide TOP1cc trapping, linking PARP activity to TOP1 function.

    Evidence Live-cell FRAP imaging, PARP inhibitor treatment, TOP1 mutagenesis (W205, N722S)

    PMID:27466387

    Open questions at the time
    • Which specific TOP1 residue(s) are PARylated was not identified
    • Whether PARP inhibitor–TOP1 synergy is clinically exploitable beyond camptothecin was not tested
  11. 2018 High

    Identification of the NORAD lncRNA–RBMX–TOP1–PRPF19-CDC5L complex (NARC1) revealed that TOP1 participates in a ribonucleoprotein complex required for genome stability and normal replication fork progression.

    Evidence RNA antisense purification with quantitative mass spectrometry, NORAD/RBMX depletion phenotypic analysis, rescue with binding-site mutant

    PMID:30150775

    Open questions at the time
    • Direct biochemical role of TOP1 within NARC1 was not dissected
    • Whether NARC1 function requires TOP1 catalytic activity was not tested
  12. 2019 High

    Identification of Apn2 as an additional nuclease resolving TOP1-derived 3′ adducts expanded the repertoire of TOP1cc repair enzymes beyond TDP1 and NER.

    Evidence In vitro biochemistry on defined 3′-adduct substrates and yeast epistasis with APN2, TDP1, RNH201 deletions

    PMID:30778235

    Open questions at the time
    • Whether mammalian APE1/APE2 perform analogous TOP1cc resolution was not demonstrated
    • Relative flux through Apn2 versus TDP1 pathways in vivo was not quantified
  13. 2021 High

    Abraxas was shown to restrict SLX4/MUS81 recruitment to TOP1cc-derived single-ended DSBs, preventing excessive end resection and aberrant break-induced replication; this placed ubiquitin-dependent regulation at the center of TOP1cc-to-DSB processing.

    Evidence Isogenic knockouts of Abraxas, SLX4, MUS81, MRE11, CtIP, RAD52, POLD3 with CPT treatment and mitotic DNA synthesis readouts

    PMID:34272385

    Open questions at the time
    • Which E3 ligase deposits the K63-ubiquitin chains counteracted by Abraxas was not identified
    • In vivo contribution to camptothecin drug response was not assessed
  14. 2022 High

    Mutational signature analysis in cancer genomes and mouse models established that TOP1 activity at genome-embedded ribonucleotides generates the characteristic ID4 deletion signature in both somatic and germline contexts, directly linking TOP1 catalysis to mutagenesis.

    Evidence Mutational signature analysis in cancer and germline data, mouse models with defective RER, TNT motif identification

    PMID:35140396

    Open questions at the time
    • Whether TOP1-mediated mutagenesis rates vary across tissues or cell types was not resolved
    • Potential protective role of accessory helicases was not examined
  15. 2022 High

    Genome-wide CRISPR screens in TDP1-KO cells confirmed MUS81 as the key nuclease generating DSBs from unresolved TOP1cc, and revealed synthetic lethality between TDP1 and APEX1/2, refining the network of TOP1cc repair pathways.

    Evidence Unbiased CRISPR screen, isogenic TDP1/MUS81 and TDP1/APEX co-deficient cell lines, DSB quantification

    PMID:35869071

    Open questions at the time
    • Whether APEX1/2 directly process TOP1cc or act indirectly was not determined
    • Pathway hierarchy under physiological versus drug-induced TOP1cc loads was not defined
  16. 2023 High

    Demonstration that transcription-associated TOP1cc generate DSBs and chromosomal translocations suppressed by TDP1 via an MRN/NHEJ-dependent pathway distinguished transcription-coupled TOP1 damage from replication-coupled damage.

    Evidence TDP1 depletion in human cells, translocation mapping, MRN and NHEJ genetic dissection

    PMID:37945566

    Open questions at the time
    • Whether specific gene loci are predisposed to transcription-coupled TOP1 translocations was not systematically mapped
    • Contribution to therapy-related secondary malignancies was not directly tested
  17. 2024 High

    CDK1-mediated phosphorylation of TDP1 at S61 was shown to be required for efficient mitotic TOP1cc repair; failure of this regulation causes MUS81-dependent fragile-site breaks and chromosome missegregation, establishing cell-cycle-dependent regulation of TOP1cc resolution.

    Evidence TDP1-S61A phospho-deficient mutant cell lines, mitotic chromosome imaging, MUS81 epistasis, CPT/aphidicolin treatment

    PMID:39014228

    Open questions at the time
    • Whether additional CDK substrates in the TOP1cc repair network exist was not addressed
    • Mitotic TOP1cc repair was not evaluated in the context of therapeutic TOP1 inhibitors
  18. 2025 High

    Functional characterization of clinical TOP1 resistance mutations (S57C, R364H, W401C, G359E) arising under ADC therapy showed reduced catalytic activity and attenuated covalent DNA binding, defining mechanisms of acquired resistance to TOP1 inhibitor payloads.

    Evidence Recombinant mutant TOP1 proteins assayed for enzymatic activity, covalent DNA binding, and drug resistance; patient plasma genotyping

    PMID:39745368

    Open questions at the time
    • Whether combination strategies can overcome these resistance alleles was not tested
    • Structural basis for resistance at each site lacks direct crystallographic data

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how TOP1 catalytic activity within the NARC1 RNP complex contributes to genome stability; the structural basis of the open-to-closed conformational transition in human TOP1; the relative pathway flux through TDP1, NER, and MUS81 routes under physiological versus drug-induced TOP1cc loads; and whether TOP1-mediated mutagenesis rates are tissue-specific.
  • No reconstitution of NARC1-dependent TOP1 function
  • No human TOP1 apo-form crystal structure
  • No quantitative in vivo measurement of pathway choice for TOP1cc repair

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140097 catalytic activity, acting on DNA 4 GO:0016853 isomerase activity 2
Localization
GO:0005694 chromosome 3 GO:0005654 nucleoplasm 1 GO:0005730 nucleolus 1
Pathway
R-HSA-73894 DNA Repair 8 R-HSA-69306 DNA Replication 4 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-4839726 Chromatin organization 2
Partners
ERCC1MUS81PARP1RBMXTDP1TOF1TOPORSXPF
Complex memberships
NARC1 (NORAD-RBMX-TOP1-PRPF19-CDC5L)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 Human TOP1 was cloned from a cDNA library; the catalytically active domain resides in the C-terminal 67.7-kDa fragment (carboxyl terminus, including active-site Tyr-723), which relaxes supercoiled DNA in vitro and shares 42% identity with yeast Top1. cDNA cloning from λgt11 expression library, in vitro DNA relaxation assay, proteolysis mapping, immunoprecipitation with anti-topoisomerase I serum Proceedings of the National Academy of Sciences of the United States of America High 2833744
1985 Yeast TOP1 (encoding DNA topoisomerase I) was cloned and shown to be a single-copy gene whose deletion is viable in haploid cells; however, combined deletion of TOP1 and the temperature-sensitive TOP2 is lethal even when mitotic arrest prevents TOP2-mediated death, demonstrating that TOP1 serves an auxiliary but distinct role in chromosome metabolism complementary to TOP2. Immunological screening of genomic library, construction of insertion/deletion mutants, cell viability assays, temperature-shift experiments with synchronised top1Δ top2-ts double mutants Proceedings of the National Academy of Sciences of the United States of America High 2997777
1998 Crystal structures of human topoisomerase I (core + C-terminal domains) in covalent and noncovalent complexes with 22-bp DNA at 2.1 Å and 2.5 Å resolution reveal that the enzyme clamps around essentially B-form DNA; the active-site nucleophile Tyr-723 is in the C-terminal domain; the core domain shares structural similarity with phage integrases; a binding site for camptothecin at the enzyme-DNA interface was proposed. X-ray crystallography at 2.1 Å (noncovalent) and 2.5 Å (covalent) resolution Science High 9488644
1998 Crystal structure of human TOP1 bound to a 22-bp DNA duplex (2.8 Å) revealed a coiled-coil linker domain protruding away from the enzyme-DNA interface; key catalytic residues were identified; the structure led to the 'controlled rotation' model for DNA relaxation, in which the downstream DNA rotates around the intact strand after Top1-mediated single-strand nicking. X-ray crystallography at 2.8 Å resolution of amino-terminally truncated TOP1–DNA complex Science High 9488652
2002 X-ray crystal structure of human topoisomerase I covalently joined to DNA and bound to the anticancer drug Topotecan (camptothecin analog) showed that Topotecan intercalates between the −1 and +1 base pairs at the cleavage site, displacing the downstream DNA and preventing religation, thereby acting as an uncompetitive inhibitor of the enzyme-substrate complex; direct drug contacts with TOP1 residues R364, D533, and N722 were identified. X-ray crystallography of ternary TOP1–DNA–Topotecan cleavage complex Proceedings of the National Academy of Sciences of the United States of America High 12426403
2002 In yeast, the tyrosyl-DNA phosphodiesterase Tdp1 and the structure-specific endonuclease Rad1-Rad10 function as two primary and redundant pathways for repairing TOP1 replicative damage (Top1 cleavage complexes at replication forks); both pathways require RAD52, RAD51, and RAD50 for subsequent recombination-dependent repair; double tdp1 rad1 mutants show TOP1-dependent growth delay and extreme camptothecin sensitivity. Yeast genetic epistasis analysis, camptothecin sensitivity assays, double-mutant construction including catalytic point mutants Proceedings of the National Academy of Sciences of the United States of America High 12368472
2007 In S. cerevisiae, Top1 and Top2 act within a ~600 bp region spanning moving replication forks to relieve torsional stress; TOP1 ablation alone does not impair fork progression or activate the Rad53 checkpoint kinase, but top1 top2 double mutants exhibit fork block, processing, and phosphorylation of Rad53 and γH2A in S-phase, demonstrating a coordinated/redundant role of both topoisomerases at replication forks. Chromatin immunoprecipitation (ChIP) genome-wide mapping of Top1 and Top2 on replicating chromosomes, genetic analysis of top1, top2 and top1 top2 mutants, checkpoint kinase assays Genes & development High 17671091
2008 Deletion of TOP1 in yeast specifically increases transcription of telomere-proximal genes and alters histone modification: loss of Top1 or expression of an inactive Y727F Top1 mutant increases H4 histone acetylation at the rDNA locus and at telomere-proximal regions; immunoprecipitation showed Top1 binds telomeric DNA repeats and is catalytically active there, indicating that Top1 catalytic activity promotes a repressed chromatin state at subtelomeric regions. Gene expression microarrays, chromatin immunoprecipitation (ChIP), yeast deletion and catalytic-point mutant analysis Journal of molecular biology Medium 18272174
2011 The SUMO-targeted ubiquitin ligase (STUbL) Rad60 and the SUMO E3 ligase Nse2 suppress spontaneous Top1 cleavage complex (Top1cc) formation in fission yeast; cells with reduced STUbL activity are dependent on Tdp1 for viability, and detection of Top1ccs by ChIP-qPCR confirmed elevated Top1ccs in cells lacking Tdp1 combined with STUbL, Rad60 or Nse2 deficiency; epistasis analyses placed STUbL/Rad60/Nse2 in the Rad16-Swi10 (NER endonuclease) pathway for Top1cc repair. Genetic epistasis, ChIP-qPCR detection of Top1cc, camptothecin sensitivity assays, fission yeast genetics PLoS genetics Medium 21408210
2014 Reversible Top1 cleavage complexes (Top1ccs) are specifically stabilized strand-specifically at the ribosomal DNA replication fork barrier (rRFB) of budding yeast in a manner requiring Fob1 and Tof2 proteins; this stabilization is replication-independent, reversible (not subject to Tdp1 or Mus81 repair), and correlates with Top1-provided rDNA stability, establishing a novel physiologically regulated mode of Top1 action at the rRFB. ChIP at engineered and native rRFB loci, genetic analysis of fob1, tof2, tdp1, mus81 mutants, strand-specific detection of Top1cc Nucleic acids research Medium 24574527
2016 PARylation of Top1 by PARP1 regulates Top1 subnuclear dynamics: PARP inhibitors (Veliparib/ABT-888) delocalize Top1 from the nucleolus to the nucleoplasm independently of Top1-PARP1 direct interaction; PARP inhibition markedly increases the CPT-induced immobile (Top1cc) fraction of Top1 across the nuclear genome; Top1 residues Trp205 and Asn722 are critical for subnuclear dynamics; the N722S mutant is restricted to the nucleolus in CPT and is deficient in CPT-induced PARylation and Top1cc formation. Live-cell imaging with GFP-tagged Top1, fluorescence recovery after photobleaching (FRAP) with kinetic modelling, PARP inhibitor treatment, site-directed mutagenesis Nucleic acids research High 27466387
2016 Top1 performs ribonucleotide-dependent deletions via a sequential double-cleavage mechanism: Top1 incises at a ribonucleotide, forming a Top1cc, and a second Top1 cleavage event creates a gap; complementarity within a tandem repeat then promotes realignment and Top1-mediated ligation to generate a deletion; parallel in vitro and in vivo analyses confirmed that deletion size is determined by the distance between two Top1 cleavage sites, and downstream complementarity promotes deletion more effectively than upstream complementarity. Parallel in vitro Top1 cleavage assays with defined substrates and in vivo yeast mutation assays; deletion mapping Nucleic acids research High 27257064
2019 Apn2 (AP endonuclease 2) in S. cerevisiae resolves Top1-mediated 3′ end blocks including phosphotyrosine-DNA conjugates (Top1cc), 2′,3′-cyclic phosphates, and their hydrolysis products; APN2 deletion suppresses 2-bp slippage mutagenesis in RNH201-deficient cells, placing Apn2 as an additional nuclease that processes Top1-induced DNA ends independently of Tdp1. Yeast genetics (deletion mutants, epistasis), in vitro biochemical assays with defined DNA substrates bearing 3′ adducts Nature structural & molecular biology High 30778235
2019 Large Top1cc-dependent deletions in yeast are produced by the nonhomologous end-joining (NHEJ) pathway and require removal of Top1 from DNA ends; these deletions accumulate in quiescent cells, suggesting that Top1-associated DSBs can arise outside of replication, with NHEJ joining ends from different Top1-associated DSBs to delete intervening sequence. Yeast genetics with NHEJ mutants, Top1cc stabilisation by top1-T722A allele and CPT, molecular characterisation of deletion junctions Proceedings of the National Academy of Sciences of the United States of America Medium 31636207
2020 In budding yeast, Top1 physically interacts with the fork protection complex component Tof1 through Tof1's C-terminal domain; this interaction is required for programmed replication fork pausing at the rDNA replication fork barrier (RFB), and Top2 can partially compensate for the absence of Top1 in this context. Physical interaction assays (Tof1-Top1 interaction), genetic analysis of tof1 mutants defective for Top1 binding, replication fork pausing assays at rDNA RFB Genes & development Medium 31896687
2021 TDP1-independent repair of Top1cc in yeast involves the nucleotide excision repair pathway components Rad16-Swi10 as alternative Top1cc repair factors; Top1cc-induced DNA damage causes hyper-recombination and checkpoint-mediated cell cycle arrest when both Tdp1 and this NER pathway are absent. Yeast epistasis genetics, ChIP-qPCR quantification of Top1ccs, checkpoint analysis NAR cancer Medium 33981998
2021 Abraxas restricts SLX4/MUS81 recruitment to CPT-induced (TOP1cc-derived) single-ended DSBs by counteracting K63-linked ubiquitin modification; without Abraxas, uncontrolled SLX4/MUS81 loading leads to excessive MRE11-CtIP-DNA2/BLM-dependent end resection and increased break-induced replication (BIR) via RAD52- and POLD3-dependent, RAD51-independent synthesis, resulting in chromosome aberrations. Genetic knockouts (Abraxas, SLX4, MUS81, MRE11, CtIP, RAD52, POLD3, RAD51), camptothecin treatment, measurement of mitotic DNA synthesis, ubiquitin modification assays Nature communications High 34272385
2022 Crystal structure of the archaeal Caldiarchaeum subterraneum CsTOP1 in apo (DNA-free) open conformation revealed that the enzyme consists of capping (CAP) and catalytic (CAT) modules connected by a flexible five-residue hinge loop; a conserved tyrosine near the hinge mediates the transition from open to closed conformation upon DNA binding; directed mutagenesis of hinge residues confirmed the importance of hinge flexibility and linked enzyme dynamics to camptothecin sensitivity. X-ray crystallography of apo-form archaeal TOP1, directed mutagenesis of hinge residues, camptothecin sensitivity assays Nature communications High 35013228
2022 Whole-genome CRISPR screens in TDP1-knockout cells identified MUS81 as a key mediator of excess DSB formation when TDP1 is absent: TDP1 KO cells show synthetic lethality with APEX1/2 deficiency but not via reduced DSB formation, indicating that TOP1cc can be either directly resolved by TDP1 or converted to DSBs and repaired by the homologous recombination pathway. Unbiased whole-genome CRISPR screens, generation of TDP1/MUS81 and TDP1/APEX co-deficient cell lines, DSB quantification Nature communications High 35869071
2022 TOP1-mediated mutagenesis at genome-embedded ribonucleotides generates a characteristic insertion-deletion mutational signature (ID4: 2–5 bp deletions at TNT motifs); defective ribonucleotide excision repair in mammals leads to accumulation of this TOP1-mediated signature both in cancer and in the germline, establishing that TOP1 activity at rNMP sites is a source of somatic and germline mutations. Mutational signature analysis in cancer genomes and germline de novo mutations, mouse models with defective ribonucleotide excision repair, identification of TNT sequence motif Nature High 35140396
2022 Exatecan forms two novel molecular contacts with the TOP1 cleavage complex beyond the three classical camptothecin interaction sites (R364, D533, N722): additional interactions with the flanking DNA base and TOP1 residue N352 result in stronger TOP1 trapping and higher DNA damage than classical camptothecin derivatives. Molecular modelling of exatecan in the TOP1 cleavage complex, comparison of TOP1 trapping and DNA damage with clinical TOP1 inhibitors, cell-based apoptosis and xenograft assays Molecular cancer therapeutics Medium 35439320
2022 TOP1 CAD-seq protocol enables genome-wide mapping of TOP1 sites of covalent engagement (cleavage complexes) with DNA using chaotropic salt enrichment and immunoprecipitation with a TOP1-specific antibody, without crosslinking, providing low-background maps of catalytically active TOP1 across the human genome. Chaotropic salt-based enrichment of TOP1-DNA adducts, anti-TOP1 immunoprecipitation, Illumina sequencing STAR protocols Medium 35942340
2023 Abortive TOP1 activity during gene transcription generates protein-linked SSBs (TOP1cc) that can lead to DSBs; these transcription-associated DSBs are a source of chromosomal translocations suppressed by TDP1; the translocations arise via an error-prone pathway requiring the MRN complex and canonical NHEJ, distinct from replication-associated TOP1 damage. Human cell TDP1 depletion, chromosomal translocation mapping, DSB mapping during transcription, MRN and NHEJ pathway genetic dissection Nature communications High 37945566
2023 MUS81 can cleave DNA-protein cross-links (DPCs) derived from TOP1, but only after TOP1 has been dislodged or partially proteolytically degraded (native full-length TOP1 blocks MUS81 cleavage); depletion of TDP1 in MUS81-KO cells confers sensitivity to CPT and affects cell proliferation only partially rescued by TOP1 depletion, indicating that MUS81 and TDP1 act in independent pathways to remove TOP1-derived lesions. In vitro MUS81 cleavage assays on DPC substrates (fluorescein, streptavidin, proteolytically processed TOP1), nuclear extract cleavage assays, TDP1/MUS81 double-KO cell viability assays, CPT sensitivity BMC biology High 37194054
2024 TOP1 and R-loops co-occupy highly transcribed cancer driver genes; depletion of R-loops (by RNase H overexpression) or depletion of TOP1 significantly reduces transcription-associated DSBs at these loci, demonstrating that TOP1 and R-loops cooperate to generate DSBs at hypertranscribed genes, contributing to early driver mutations in cancer. DSB mapping, R-loop mapping (DRIP-seq), TOP1cc mapping, TOP1 and RNase H depletion experiments in cancer cells iScience Medium 38375218
2024 CDK1 phosphorylates TDP1 at residue S61 during mitosis to promote repair of trapped Top1cc (Top1-DNA covalent complexes); a TDP1-S61A phospho-deficient variant is trapped on mitotic chromosomes and causes DNA damage and mitotic defects; Top1cc repair in mitosis occurs through a MUS81-dependent mechanism; replication stress leads to TDP1-S61A enrichment at common fragile sites, causing MUS81-dependent chromatid breaks, anaphase bridges and micronuclei. Identification of CDK1 phosphorylation site by mutagenesis, phospho-deficient TDP1-S61A cell lines, mitotic chromosome imaging, MUS81 epistasis, camptothecin/aphidicolin treatment The EMBO journal High 39014228
2025 TOP1 resistance mutations (S57C, R364H, W401C, G359E) arising in metastatic breast cancer patients after ADC treatment show reduced enzymatic activity, attenuated covalent DNA binding, and resistance to TOP1 inhibitor payloads SN-38 and deruxtecan, establishing these as gain-of-function resistance alleles at structurally important positions. Plasma-based genotyping from patients progressing on ADC therapy, functional characterisation of recombinant TOP1 mutant proteins (enzymatic activity, covalent DNA binding, drug resistance assays) Clinical cancer research High 39745368
2018 Human TOP1 residues 236 and 237 are required for interaction with BTBD2 (and BTBD1); replacement of these residues with the African Green Monkey counterparts abolishes both the infectivity enhancement of progeny HIV-1 virions and the TOP1-BTBD2 interaction, suggesting TOP1 modulates HIV-1 viral tropism through its interaction with BTBD2 in cytoplasmic bodies. Co-immunoprecipitation of TOP1 with BTBD1/BTBD2, site-directed mutagenesis of TOP1 residues 236–237, HIV-1 infectivity assays in AGM and human cells, RNAi knockdown of BTBD2 Virology journal Medium 21092135
2018 The NORAD lncRNA assembles a topoisomerase complex (NARC1) containing TOP1, ALYREF, and the PRPF19-CDC5L complex through interaction with RBMX; depletion of NORAD or RBMX leads to chromosome segregation defects, reduced replication-fork velocity, and altered cell-cycle progression linked to TOP1 and PRPF19-CDC5L function; NORAD acts by modulating the ability of RBMX to assemble this ribonucleoprotein complex. RNA antisense purification combined with quantitative mass spectrometry, NORAD/RBMX depletion with phenotypic analysis (chromosome segregation, replication fork velocity, cell cycle), rescue experiments with RBMX-binding site deletion Nature High 30150775
2015 The ERCC1-XPF endonuclease together with RPA can cleave 3′-phosphotyrosyl bond nick DNA lesions mimicking Top1cc in vitro; ERCC1-XPF and RPA co-localize at CPT damage sites in vivo; NER factors including ERCC1-XPF, RPA, DNA polymerase δ, FEN1, and DNA ligase 1 together support repair synthesis of Top1-attached nick DNA lesions, establishing an NER-related repair pathway for Top1cc. In vitro nuclease activity assays on phosphotyrosyl-nick DNA substrate, EMSA, co-localization by immunofluorescence in CPT-treated cells, in vitro DNA repair synthesis reconstitution Carcinogenesis High 26025908
2026 In vertebrate (chicken DT40) cells, TOP1 and TOP2 have complementary roles in DNA replication: depletion of TOP1 alone or inhibition of TOP2 alone does not impair replication fork progression, but combining TOP1 depletion with TOP2 inhibition nearly abolishes DNA replication, causing S-phase arrest and apoptosis; additionally, TOP2 poison etoposide (but not the TOP2 inhibitor ICRF193) in TOP1-depleted cells causes G1/early S-phase arrest, implicating TOP1 in replication initiation. Conditional TOP1 knockout in DT40 cells, ICRF193 (TOP2 inhibitor) and etoposide (TOP2 poison) treatment, DNA replication rate measurement, cell-cycle analysis The Journal of biological chemistry High 41791707
2002 Top1 activity promotes repressed chromatin at the rDNA locus in S. cerevisiae: deletion of TOP1 causes increased histone acetylation at the rDNA locus similar to sir2 deletion; in both top1 and sir2 mutants, rDNA chromatin becomes more accessible. Chromatin accessibility assays and histone acetylation analysis at rDNA locus in top1Δ and sir2Δ yeast strains Journal of molecular biology Medium 12215413
1999 The t(11;20)(p15;q11) chromosomal translocation in therapy-related MDS produces a chimeric NUP98-TOP1 mRNA in which the N-terminal FXFG repeat region of NUP98 is fused in-frame to the body of TOP1 (from exon 8 onwards), identifying TOP1 as a recurrent translocation target in haematological malignancies; the NUP98 FXFG domain is separated from its RNA-binding domain by the breakpoint. Molecular cloning of translocation breakpoint, RT-PCR, sequencing of chimeric transcript Blood Medium 10556215
2025 TOPORS, a SUMO E3 ligase/ubiquitin ligase, promotes SUMO1 modification (SUMOylation) of TOP1 in macrophages; knockdown of TOPORS reduces SUMO1-TOP1 levels and increases TOP1 protein and γH2AX (DNA damage marker) in ovalbumin-stimulated macrophages, indicating that TOPORS-mediated SUMO1 modification of TOP1 facilitates DNA damage repair in oxidative stress conditions. Immunoprecipitation to detect SUMO1-TOP1 conjugates, TOPORS knockdown (RNAi), γH2AX immunofluorescence, OVA-stimulated macrophage model Toxicology letters Medium 40532862

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2873 20686565
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2005 Nucleolar proteome dynamics. Nature 934 15635413
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
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